title: Mutated mitofusin 2 presents with intrafamilial variability and brain mitochondrial dysfunction.
abstract: BACKGROUND
  The axonal forms of Charcot-Marie-Tooth (CMT2) disease are a clinically and genetically heterogeneous group of disorders. Mitofusin 2 gene (MFN2) mutations are the most common cause of CMT2. Complex phenotypes have been described in association with MFN2 gene mutations, including CMT2 with pyramidal features (hereditary motor and sensory neuropathy [HSMN V]) and CMT2 with optic atrophy (HMSN VI).
  
  
  OBJECTIVE
  To report on the clinical, neurophysiologic, and neuropathologic features of an Italian family with a novel MFN2 gene mutation and investigate brain functional parameters using magnetic resonance spectroscopy (MRS).
  
  
  METHODS
  Three family members, a father and his two sons, were affected by peripheral neuropathy, cognitive impairment, and poor nocturnal vision (also optic neuropathy in one case). A member of this family also showed spastic paraparesis. The MFN2 gene sequence was analyzed. A sural nerve biopsy as well as brain (1)H-MRS and (31)P-MRS were evaluated in two patients.
  
  
  RESULTS
  Affected family members carried a novel MFN2 missense mutation, namely R104W, located within the critical GTPase domain of the protein which affects a highly conserved amino acid position. Sural nerve biopsies showed a normal mitochondrial network, particularly at the nodes of Ranvier, upon electron microscopy examination. A significant defect of high energy phosphates (HEPs) in the visual cortex was observed at rest by (31)P-MRS in the adult proband, while his son showed a defective recovery of HEPs after stimulation of the visual cortex.
  
  
  CONCLUSIONS
  Cognitive impairment may be another feature of the MFN2-related phenotype. The widespread peripheral and CNS involvement, as well as the neurosensorial defects, underline the similarities among MFN2-related and primary mitochondrial disorders.
authors.affiliation: Dino Ferrari Centre, Department of Neurological Sciences, University of Milan, IRCCS Foundation Ospedale Maggiore Policlinico Mangiagalli and Regina Elena, Milan, Italy.
authors.forename: R
authors.initials: R
authors.lastname: Del Bo
authors.forename: M
authors.initials: M
authors.lastname: Moggio
authors.forename: M
authors.initials: M
authors.lastname: Rango
authors.forename: S
authors.initials: S
authors.lastname: Bonato
authors.forename: M G
authors.initials: MG
authors.lastname: D'Angelo
authors.forename: S
authors.initials: S
authors.lastname: Ghezzi
authors.forename: G
authors.initials: G
authors.lastname: Airoldi
authors.forename: M T
authors.initials: MT
authors.lastname: Bassi
authors.forename: M
authors.initials: M
authors.lastname: Guglieri
authors.forename: L
authors.initials: L
authors.lastname: Napoli
authors.forename: C
authors.initials: C
authors.lastname: Lamperti
authors.forename: S
authors.initials: S
authors.lastname: Corti
authors.forename: A
authors.initials: A
authors.lastname: Federico
authors.forename: N
authors.initials: N
authors.lastname: Bresolin
authors.forename: G P
authors.initials: GP
authors.lastname: Comi
mesh_terms: D000328:Adult; D001706:Biopsy; D001928:Brain Diseases, Metabolic / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D002607:Charcot-Marie-Tooth Disease / Q000150:complications* / Q000235:genetics* / Q000378:metabolism; D002648:Child; D003072:Cognition Disorders / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D004252:DNA Mutational Analysis; D004734:Energy Metabolism / Q000502:physiology; D020558:GTP Phosphohydrolases; D020022:Genetic Predisposition to Disease / Q000235:genetics; D005820:Genetic Testing; D006579:Heterozygote; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D028361:Mitochondrial Diseases / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D024101:Mitochondrial Proteins / Q000235:genetics*; D020125:Mutation, Missense; D010710:Phosphates / Q000378:metabolism; D013497:Sural Nerve / Q000473:pathology; D014786:Vision Disorders / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D014793:Visual Cortex / Q000378:metabolism / Q000503:physiopathology
chemical_list: D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D010710:Phosphates; D020558:GTP Phosphohydrolases; C470018:MFN2 protein, human